Rachel Lennon, BMedSci BMBS PhD FRCPCH
Glomerular cell adhesion
Our kidneys are highly sophisticated organs responsible for excreting waste products as well as contributing to the control of blood pressure, the maintenance of healthy bones and to the production of red blood cells. Each kidney has about a million tiny kidney filters, known as glomeruli, which allow water and small molecules to pass freely but prevent cells and large molecules from leaving the circulation. The persistent loss of protein molecules from the blood into the urine is an early sign of glomerular kidney disease and for many individuals there is a relentless progression to kidney failure. The worldwide incidence of glomerular disease is increasing dramatically, linked to increases in obesity and type 2 diabetes. Therefore early detection and targeted treatments are high priorities for the international research community; however before such approaches are developed, it is necessary to understand basic underlying mechanisms of disease.
The study of glomerular disease in children has yielded important discoveries, which have improved our understanding of the mechanisms of disease. Such discoveries have highlighted the importance of specialised cells known as podocytes and we now understand that the complex of proteins connecting adjacent podocytes is critical for maintaining the integrity of the glomerular filters. Although evidence is evolving, there are still many unanswered questions about how specialised glomerular cells form interactions with neighbouring cells and how they interact with the network of proteins outside of cells, known as the extracellular matrix.
This laboratory is using mass spectrometry-based proteomics to interrogate protein complexes in the glomerulus. By systematically examining the interactions between cells, extracellular matrix and the associated signalling networks, our work aims to develop current understanding about this unique molecular landscape, and to appreciate how these networks change in disease. With greater understanding about the pathways involved it will be possible to consider ways in which new treatments could stop or even reverse kidney disease.
The scientific story
The glomerular capillary wall is a highly sophisticated filter (Figure 1A) comprised of specialised cells and extracellular matrix (ECM). In glomerular disease the filtration barrier becomes permeable to macromolecules and this state is associated with dramatic changes in cell morphology and ECM, yet these changes are not understood at the molecular level.
Normal glomerular barrier function requires tight regulation of cell adhesion and in this laboratory we focus on both the cell-matrix interface and the unique podocyte cell-cell junction. Cell adhesion is intimately linked to the extracellular environment (Figure 1B) and in the glomerulus this is a complex niche, providing a structural scaffold and signalling platform for the specialised glomerular cells. The molecular composition of this niche has been traditionally investigated by candidate-based approaches, which have led to the identification of key components including laminins, collagen-IV, nidogens and heparan sulphate proteoglycans. With newer global approaches it is possible to take an unbiased approach to investigating ECM and we have used mass spectrometry-based proteomics to investigate the human glomerular ECM. We found a complex network of 144 structural and regulatory ECM proteins in the normal glomerulus and in addition we identified compositional change associated with glomerular dysfunction. Coupled to these compositional changes we also observed structural changes in the glomerular ECM with 3View electron microscopy (Figure 2).
Our ongoing aims are to use global approaches and imaging techniques to build understanding about cell adhesion in the glomerulus and to appreciate how adhesion and matrix become dysregulated. Ultimately we aim identify new therapeutic targets for adults and children with glomerular disease.